Protective role of thiols in cyclophosphamide-induced urotoxicity and depression of hepatic drug metabolism.
One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
D000111:Acetylcysteine / Q000494:pharmacology*; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced; D008099:Liver / Q000201:enzymology; D008297:Male; D008623:Mercaptoethanol / Q000031:analogs & derivatives*; D015080:Mesna / Q000494:pharmacology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D001743:Urinary Bladder / Q000187:drug effects*
D008623:Mercaptoethanol; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D001189:Aryl Hydrocarbon Hydroxylases; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase; D015080:Mesna; D000111:Acetylcysteine